This proposal will examine the regulation of innate immunity, using infection of mice with the NIAID Category B Priority Pathogen, Toxoplasma gondii, as a model system. Our prior studies have established an important protective role for innate immunity in T. gondii infection, but little is known about its regulation. In contrast, current studies have revealed important features regarding regulation of acquired immunity. In several models, acquired T cell-dependent immunity has been found to be regulated by inhibitory CD4+CD25 + T cells (Treg) that mediate their effects via IL-10, CTLA-4, and/or TGF-beta. T cell-dependent immunity can also be regulated by catabolites produced as a result of induction of the enzymes indoleamine-2,3-dioxygenase (IDO) and heme oxygenase (HO). Our preliminary studies show that IL-10, TGF-beta, IDO and HO mRNAs are induced in several organs during acute T. gondii infection. In this proposal, we will test the hypothesis that Treg cells, the cytokines they produce, and the enzymes IDO and HO are significant regulators of NK cell- and neutrophil-dependent innate immunity to T. gondii. Thus, these studies will determine whether components of innate resistance to infection are regulated, or can be regulated, by any of several likely cellular and molecular candidates. The consequences of regulation will be determined at the cellular and molecular level. Elucidation of the mechanistic basis of regulation of innate immunity will lead to a fuller understanding of resistance to acute infection. Moreover, innate immunity significantly affects the generation of acquired immunity to many infections. Thus, the proposed studies will form a foundation on which to build future studies to examine how regulation of innate immunity impacts acquired immunity to infection and vaccination.